Direct compression vehicles

ABSTRACT

Direct compression vehicle useful for preparation of tablets by the direct compression technique is obtained by dispersing a diluent such as sugar, in a fully hydrated hydratable polymer, such as starch, drying the resulting dispersion, and reducing the dried product to particles of the desired size. The vehicle can be admixed with the active material and, if desired, a lubricant, and the resulting mixture compressed without prior granulation or slugging to form a tablet.

States Patent Monti et all,

DIECT COMPRESSION VEHICLES Anthony Monti, lrvington; John P. Troy,Hicksville, both of N.Y.; Charles B. Brueg,

Inventors:

Short Hills, NJ.

Assignee: SuCrest Corporation, NY, NY.

Filed: Apr. 29, 1969 Appl. No.: 820,283

[1.5. Ci ..127/29, 8/79, 99/26, 99/134 R, 99/141 A, 127/63, 264/122,424/154, 424/156, 424/157, 424/158, 424/230, 424/280, 424/358, 424/361,424/362, 424/363 Int. Cl. ..Cl3f 3/00 Field oi Search ..127/29, 30, 63;99/134 R References Cited OTHER PUBLICATIONS Little d M tshe ,f a l WW5.$999"? Feb. 1, 1972 tion, 44- 53, The Northern Publishing Co., Ltd.Liverpool, 1963.

Primary Examiner-Morris O. Wolk Assistant Examiner-Sidney MorantzAtt0rneyl(enyon & Kenyon Reilly Carr & Chapin [5 7] ABSTRACT 10 Claims,No Drawings DIRECT COMPRESSION VEHICLES This invention relates to directcompression vehicles. More particularly, this invention relates to aparticulate composition which can be admixed with an active andoptionally, a lubricant, and the resulting mixture directly compressedinto a tablet without the necessity of granulation or slugging of themixture.

There are two general methods for forming tablets, i.e., compression ofa dry particulate material and trituration, or molding of a moistmaterial, of which the first technique is by far the most frequentlyemployed. The-compression technique may be further subdivided into threemajor categories, viz direct compression, wet granulation and drygranulation. The direct compression technique is the most desirable, inthat it employs the fewest steps and, in the case of the production oftablets containing sensitive or unstable actives, such as certainpharmaceuticals, minimizes the exposure to water or other conditionstending to adversely affect stability of the active. Unfortunately,however, it has been found that the direct compression technique is oflimited applicability.

First, most active materials possess poor compression pro perties, andthus are unsuitable for this technique. In addition, many actives arerequired in such small amounts per unit dosage form that directcompression of the active alone is im practical, if not impossible. As aresult, the active must be admixed with a direct compression vehicle,i.e., an inert composition which is compatible with the active and hasgood compressibility. In addition, the direct compression vehicle shouldhave good flowability, good stability under normal ambient conditions,no adverse effect on tablet disintegration time, the ability to producegood table surfaces, and low cost.

To date, however, no material has been found which satisfies all ofthese criteria. For example, of the most popular of such compressionvehicles, spray-dried lactose possesses poor stability and discolors onstoring, dicalcium phosphate provides tablets having poor strength, andmicrocrystalline cellulose is expensive.

It is an object of the present invention to provide a new directcompression vehicle.

It is a further object of this invention to provide a multicomponentcompression vehicle which may be combined with an active and, ifdesired, a lubricant, and the resulting dry mixture subjected to directcompression.

The direct compression vehicles of the present invention comprise minuteparticles of a dispersion of certain watersoluble or dispersible inertdiluents in a matrix ofa hydratable high polymer.

The diluent can be any normally solid material, i.e., any material whichis solid under conditions of normal atmospheric pressures andtemperatures, provided it is inert, edible and permissable in the tableformed from the direct compression vehicle. Thus, it can bewater-soluble or insoluble in water. If insoluble, however, it must becapable of reduction to a size which is useful in the direct compressionvehicle of this invention, i.e., a size below about 200 mesh, andpreferably below about microns.

Preferred diluents include normally saccharine materials, i.e., a monoor disaccharide such as glucose, mannose, galac tose, fructose,arabinose, xylose, sucrose, maltose and lactose; as well as certainpolyols of the formula HOCHACI-IOHMCH OH wherein .x is 1-4, such asglycerol, erythritol, arabitol, xylitol, adonitol, mannitol, dulcitoland sorbitol. In addition, certain salts may be employed, includingsodium chloride, sodium citrate, calcium carbonate, calcium sulfate andtricalcium phosphate. The diluent may be one or a mixture of two or moreof the aforesaid substances. In the event the diluent is a sugar, it maybe of synthetic or natural origin, and may be supplied to the mixingstep in the form ofa solution or syrup, such as molasses, affinationsyrup, invert syrup and the like.

The hydrated polymer includes hydrophilic polysaccharides, hydrocolloidsor proteinaceous materials which, although not soluble in water, arehydrated upon admixture with water, and when substantially fullyhydrated form a clear aqueous sol of swollen polymer and water.Illustrative examples of these high polymers include starch, agar,locust bean gum, carrageen, dextrin, cereal flour and the like.

The polymer, diluent and water are admixed in any convenient manner andin proportions such that there is obtained a substantially clear fluidmixture comprising an aqueous solution or dispersion of diluentdispersed throughout the swollen hydrated polymer. The preciseconditions and proportions will vary widely, depending upon the polymeremployed, and the amount of and additive employed.

The amount of water necessary to hydrate the hydrophilic polymer iseither known or is readily determined by the simple experiment of addingwater in known amount to a known amount of dry polymer until a clear solis obtained. in general, at least about 8 parts of water are requiredper part of starch or dextrin, at least about 25 parts of water arerequired per part of locust bean gum, and at least about 33 of water arerequired per part of agar and carrageen. The foregoing amounts of waterprovide tablets of optimum strength, but lesser amounts of water, forexample as low as 50 percent or more of the above values, can beemployed and still obtain a useful tablet.

When the diluent is insoluble in water, no additional water is required.When, however, the diluent is water-soluble, enough additional watermust be employed to dissolve the additive. For example, if sucrose isadded to a clear, fully hydrated starch the resulting mixture becomesmore fluid because the sucrose has a greater affinity for water thanstarch, and thus removes some of the water of hydration. If, however, inaddition to the 8 parts water per part starch neces sary for fullyhydration, there is added at least 0.5 part water per part sucrose toensure solution of the sucrose, the starch remains hydrated. Althoughgreater quantities of water can be employed if desired, they areunnecessary and, in fact, are dis advantageous in increasing the heatload for drying and may preclude the use of certain drying techniques,such as drum drying, which require a relatively viscous. liquid.

The ratio of water-soluble additive to hydratable polymer can varywidely, depending upon the particular materials employed and thecharacteristics desired in the product direct compression vehicle. Ingeneral, however, ratios offrom about 0.25 to about 250 parts ofadditive per part of polymer, preferably from about 2 to about 50 partsadditive per part of polymer, are useful. Ratios of from about 20 toabout 30 parts additive per part of polymer are most preferred.

Drying of the resulting dispersion may be effected by a variety oftechniques, such as spray drying, tray drying, drum drying and the like.In a preferred technique, the dispersion is dried by deposition on aheated surface to effect evaporation and convert the dispersion into adry, hot, plastic film, remov' ing the film from the heated surface andattenuating the film while simultaneously cooling it, to convert theplastic film to a brittle or frangible condition. After the film hasbeen thus cooled, it is fragmented and ground to a desired particle sizeand the ground product is employed. In this technique, the mixture ofhydratable polymer and diluent should, of course, have the property ofbeing plastic when in a hot, dry state.

A preferred way to practice the method of this invention is through theuse of a heated drum dryer and a cooled rotary takeoff reel located aslight distance therefrom with a current of cooling air passingtherefrom.

In such a process the dispersion of the aqueous solution of a saccharinematerial and the high polymer is prepared and introduced into the nipbetween a pair of steam-heated oppositely rotating drums at a rate toeffect rapid evaporation of the water, but without permitting theresultant dehydrated product, which contains not more than 4 percentmoisture, and which forms a relatively thick plastic film on thesurfaces of the drums, to reach a temperature at which destructivedecomposition would begin. Thus, the temperature of the dehydratedmaterial should not exceed about 350 F. and the operating conditions ofthe drums should be adjusted accordingly. At the line of transfer to thereel, which is rotating with a peripheral speed greater than that; ofthe drum, the hot dehydrated film is removed by a doctor blade from itsassociated drum and transferred to the reel across a current of coolingair, having a 60-80 F. temperature, which effects an initial cooling'ofthe dehydrated material to near room temperature. This cooling effect isenhanced by the thinning or drawing down of the film as a consequence ofhaving the reel operate at the greater peripheral speed. Since the reelis also cooled by 60-80 F. air, the thin film is further cooled to aroom temperature of about 70 F. to about 95 F. and the cooling air atthe line of removal of the film from the reel aids both its removaltherefrom and a final cooling to a brittle or frangible state. Thefrangible film then drops away from the reel as a brittle sheet orfragments onto a conveyor for transport to a storage bin or to acomminuting device for reduction to the desired particle size for directtabletting.

If only one takeoff reel is used, it will, of course, be necessary toprovide a scraper or other means on the opposite drum to prevent passageof the hot dehydrated film therearound and force it over onto the otherdrum.

Although in the foregoing description of the method mention has beenmade ofa two-drum dryer with either a single or two takeoff reels, itwill be appreciated that a single drum dryer with a single takeoff reelcan be used with equal effectiveness.

The dried product is broken up into particles having the desireddimensions and, if necessary, screened to achieve the proper size rangeand distribution. The resulting particulate product comprises minuteparticles of the water-soluble additive dispersed throughout thehigh-polymer matrix, and is substantially different in appearance andproperties from mixtures of the same dry materials which are obtained bydry blending, or even wet granulation techniques. The reason for thedifference is that none of the heretofore known techniques for preparingtabletting materials or blends employ sufficient water to both hydratethe polymer and dissolve the additive. On the other hand, U.S. Pat. No.2,963,373 to Monti et al. dis closes an icing percursor comprising agaror carrageen and starch and/or sugar which is prepared according to theforegoing technique, and it has been found that the resulting product isan excellent direct compression vehicle in accordance with thisinvention. Other previously known products which may be employed asdirectly compressible vehicles are the modified polysaccharide gums ofMonti et al. disclosed in U.S. Pat. No. 3,042,668.

The granular direct compression vehicle of this invention is admixedwith the active which it is desired to incorporate into tablet form and,if necessary, a lubricant, and the mixture tabletted by known directcompression procedures. The proportions of vehicle, active and lubricantare not critical, and obviously depend upon the active and the unit dosedesired in the tablet. In general, however, the directcompressionvehicle will comprise at least percent of the tablettingmixture, and thus the resulting tablet, although amounts within therange of from about 70 percent to about 95 percent are most common.

By the term active material is meant any material intended for ingestionhaving a beneficial or desirable effect on the user. Suitable activematerials include therapeutic materials, such as anesthetics,antibiotics, antitussives, vitamins, aspirin, antacids, and the like;foodstuffs such as cocoa, dried oats, fruit flakes and the like; edibledyes and other food additives; and so on. The vehicle is a free-flowinggranular material and imparts improved flow characteristics to theactive material and other components of the blend, thereby assuring easeof tabletting.

The blend of direct compression vehicle, active material and otheradditives is mixed and directly compressed to form a tablet employingconventional techniques and apparatus.

The following examples are illustrative. Unless otherwise specified, allparts and percentages are by weight.

EXAMPLE 1 A mixture of 182 pounds of sucrose, 35 pounds of tapiocaflour, 300 pounds of starch and 400 gallons of water was heated to 180F., and 714 pounds ofa 70 percent invert syrup was added. The resultingmixture was 'drum dried to a moisture content of about 2.13 percent, andthen broken up into flakes of about one half an inch. The resultingparticulate flake material was admixed with calcium stearate in a ratioof 99 parts to 1 part and after pulverization to yield a product havinga particle size of below about 200 mesh percent through 200 mesh),compressed to form l3/32-inch, 0.5-gram tablets at 1,000 and 3,000. Theresulting tablets had Stokes hardnesses of 3.25 and 4.1 kilograms,respectively, and evidenced no capping.

EXAMPLE 2 Employing procedures similar to those described in example l,a flake product containing about 46 parts invert sugar, 25 parts starch,28 parts sucrose and 1 percent water was produced and admixed withCab-O-Sil brand silica gel to provide a mixture containing 98 partsflake and 2 parts silica gel. The resulting mixture, after pulverizing,was tabletted at 3,000 and 9,000 p.s.i. The tablets produced at 3,000p.s.i. were ejected at a pressure of 100 p.s.i., evidenced only slightcapping and had a hardness of 19.5. At 9,000 p.s.i. and ejectionpressure of 350 p.s.i. no capping was observed and tablet hardness wasin excess of 45 kg.

In a second run equal parts of the flake and sucrose were mixed andpulverized, and then magnesium stearate was blended in to provide 49parts each of flake and sucrose and 2 parts magnesium stearate. Tabletscompressed at 3,000 p.s.i. and ejected at 60 p.s.i. had a hardness of20.75 and evidenced no capping, and those compressed at 9,000 p.s.i. andejected at 95 p.s.i. had a hardness of 37.5 kg. and evidenced nocapping.

EXAMPLE 3 Employing procedures similar to those described in example l,a mixture of 350 pounds of starch and 284 pounds sucrose in 450 gallonsof water and 571 pounds of 70 percent invert sugar was drum dried toabout 2 percent moisture and crushed to form flakes having a size ofabout one-half an inch. The resulting product, after further pulverizingto below about 200 mesh, was compressed at 3,000 and 9,000 p.s.i. and 35p.s.i. ejection pressure to form l3/32-inch tablets weighing 0.5 grams.Tablet hardness was 38.5 and greater than 45, respectively, and nocapping was observed.

The flake product was admixed with sucrose and calcium stearate toprovide a mixture containing 60 parts flake, 39

parts sucrose and 1 part stearate, and the resulting mixture tabletted.At 3,000 psi. the ejection pressure was 50 p.s.i. and tablet hardnesswas 13.5. At 9,000 p.s.i. the ejection pressure was 45 p.s.i. and tablethardness was 22. No capping was observed at either pressure.

EXAMPLE 4 Employing procedures similar to those described in example l,a flake product containing 22.5 percent invert sugar, 42.4 percentsucrose, 32.1 percent starch and 3 percent moisture was blended to forma mixture of 66.6 parts flake, 32.35 parts sucrose and 1.0 parts calciumstearate. Tablets pressed at 1,000, 3,000 and 9,000 p.s.i. hadhardnesses of 6.5, 14.5 and 23.0, respectively.

EXAMPLE 5 Employing procedures similar to those described in example 1,a mixture of 1 part locust bean gum, 25 parts sugar and 100 parts waterwas heated to F. and drum dried to less than 1 percent moisture andreduced to /z-inch flakes. The resulting product, after pulverization toa product of less than about 200 mesh, was compressed at 4,500 p.s.i. toform a tablet having a hardness of greater than 42 kg.

EXAMPLE 6 Employing procedures similar to those described in example l,a mixture of 4 parts of agar, 70 parts sucrose and 200 parts water wasboiled and then drum dried and flaked. After pulverizing, the productwas compressed at 4,500 p.s.i. to form a tablet having a hardness ofgreater than 42 kg.

EXAMPLE 7 Employing procedures similar to those described in example 1,a mixture of 4 parts carrageen, 70 parts sucrose and 200 parts water wasdrum dried and flaked. The flake product, after pulverizing, wascompressed at 4,500 psi. to form a tablet having a hardness of greaterthan 42 kg.

Each of the direct compression vehicles of the foregoing examples can beblended in accordance with the following recipes and compressed to formtablets or wafers.

CONFECTIONERY TABLETS OR WAFERS l. Leinon-flavorcd confectionery tablet:

100.0 pt. direct compression vehicle 10 pt. citric acid, dry 0.25 pt.encapsulated lemon flavor 0.10 pt. yellow color No.5

1.0 pt. magnesium stearate 2. Grape-flavored confectionery tablet:

500 pt. direct compression vehicle 50.0 pt. 6X powdered sugar 20 pt.tartaric acid 0.25 pt. grape flavor 0.05 pt. grape color pt. calciumstearate 3. Cherry-flavored confectionery tablet:

100.0 pt. direct compression vehicle 2.0 pt. fumaric acid 0.2 pt. cherryflavor 0.1 pt. red color pt. magnesium stearate B. PHARMACEUTICALFORMULATIONS l. 50.0 pt. direct compression vehicle 37.5 pt. aluminumhydroxide l.0 pt. magnesium stearate 2. 100.0 pt. direct compressionvehicle 25.0 pt. calcium carbonate 5.0 pt. magnesium carbonate I droppeppermint oil 2.0 pt. magnesium stearute 3. 100.0 pt. directcompression vehicle 25.0 pt. acetyl salicylic acid 150 pt. corn starch2.0 pt. magnesium stearale 4. 90.0 pt. direct compression vehicle 10.0pt. vitamin C in dry form 2.0 pt. magnesium stearate Other activeingredients of use in blends with the direct compression vehicle are:sodium bicarbonate, acetanilid, phenacetin, and magnesium trisilicate.

C. SPECIALTY PRODUCTS 1. lnvertase sugar tablet 964 pt, directcompression vehicle 3.6 pt. liquid triple strength invertase (K=0.9)

1.0 pt. magnesium stearate 2. Cocoa-sugar tablet 900 pt, directcompression vehicle 10.0 pl. high fat cocoa 0.2 pt. dcndritic salt 1.0pt. magnesium stearate After blending, the mixture is tablette-rl toform a cocoa-sugar tablet.

3. Sugar-synthetic sweetener tablet 450.0 pt. direct compression vehicle7.16 pt. calcium cyclamatc 0.8 pt. sodium saccharin 5.0 pt. calciumstearatc 4. Highly concentrated color tablet 90.0 pt. direct compressionvehicle 10.0 pt. dried yellow FD&C No. 6 pt. sodium benzoate 5. YeastFood Tablet 34.0 pt. calcium sulfate (2H 0) 23.0 pt. flour 9.0 pt.ammonium chloride 025 pt. potassium hromate 1775 pt. sodium dihydrogenphosphate l6.0 pt. salt 900.0 pt. direct compression vehicle 10.0 pt.magnesium stcarate What is claimed is:

1. In a method for producing a tablet by the direct compression of amixture including an active material and a direct compression vehicle,the improvement of employing a dry granular direct compression vehiclecomprising an inert, edible diluent dispersed throughout a matrix of ahydratable polymer prepared by mixing said diluent and said polymer withwater in proportions sufficient to provide a substantially fluid mixtureof an aqueous solution or dispersion of diluent dispersed throughoutswollen, hydrated polymer, and thereafter drying said mixture, andforming particles therefrom.

2. A method according to claim 1 wherein said diluent is selected fromthe group consisting ofa monosaccharide, a disaccharide, a polyol of theformula HOCH. (CHOH) ,.CH OH wherein x is 1 to 4, sodium chloride,sodium citrate, calcium carbonate, calcium sulfate or tricalciumphosphate.

3. A method according to claim 1 wherein said hydratable polymer isselected from the group consisting of starch, agar, locust bean gum,carrageen, dextrin or cereal flour.

4, A method according to claim 1 wherein the ratio of diluent to polymeris from about 0.25 to about 250 parts by weight diluent per part ofpolymer.

5. The tablet produced by the process of claim 1.

6. A dry, granular direct compression vehicle comprising an inert,edible diluent dispersed throughout a matrix of starch prepared bymixing said diluent and starch with water in proportions sufficient toprovide a substantially fluid mixture of an aqueous solution ordispersion of diluent dispersed throughout swollen, hydrated starch, andthereafter drying said mixture and forming particles therefrom.

7. A vehicle according to claim 6 wherein said diluent is selected fromthe group consisting of a monosaccharide, a disaccharide, a polyol ofthe formula HOCH (CHOH),CH OH wherein x is l to 4, sodium chloride,sodium citrate, calcium carbonate, calcium sulfate or tricalciumphosphate.

8. A vehicle according to claim 6 wherein said diluent is present in anamount of from about 0.25 to about 250 parts per part of starch.

9. A vehicle according to claim 8 wherein said diluent is selected fromthe group consisting of a monosaccharide or a disaccharide.

10. A vehicle according to claim 8 wherein said diluent is selected fromthe group consisting of sucrose or invert sugar.

2. A method according to claim 1 wherein said diluent is selected fromthe group consisting of a monosaccharide, a disaccharide, a polyol ofthe formula HOCH2(CHOH)xCH2OH wherein x is 1 to 4, sodium chloride,sodium citrate, calcium carbonate, calcium sulfate or tricalciumphosphate.
 3. A method according to claim 1 wherein said hydratablepolymer is selected from the group consisting of starch, agar, locustbean gum, carrageen, dextrin or cereal flour.
 4. A method according toclaim 1 wherein the ratio of diluent to polymer is from about 0.25 toabout 250 parts by weight diluent per part of polymer.
 5. The tabletproduced by the process of claim
 1. 6. A dry, granular directcompression vehicle comprIsing an inert, edible diluent dispersedthroughout a matrix of starch prepared by mixing said diluent and starchwith water in proportions sufficient to provide a substantially fluidmixture of an aqueous solution or dispersion of diluent dispersedthroughout swollen, hydrated starch, and thereafter drying said mixtureand forming particles therefrom.
 7. A vehicle according to claim 6wherein said diluent is selected from the group consisting of amonosaccharide, a disaccharide, a polyol of the formulaHOCH2(CHOH)xCH2OH wherein x is 1 to 4, sodium chloride, sodium citrate,calcium carbonate, calcium sulfate or tricalcium phosphate.
 8. A vehicleaccording to claim 6 wherein said diluent is present in an amount offrom about 0.25 to about 250 parts per part of starch.
 9. A vehicleaccording to claim 8 wherein said diluent is selected from the groupconsisting of a monosaccharide or a disaccharide.
 10. A vehicleaccording to claim 8 wherein said diluent is selected from the groupconsisting of sucrose or invert sugar.